Department of Epidemiology, School of Public Health and Comprehensive Cancer Center and Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, CA, USA.

15

Julius Center for Health Sciences and Primary Care and Department of Medical Genetics and of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, PA, USA, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Department of Population Health and Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA.

32

Westat, Rockville, MD, USA.

33

Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.

34

Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.

Abstract

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.

Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Plots of the effect of each variant on telomere length and NHL risk overall and by the subtype. The X axis (G–X association) plots the previously published linear regression β-estimates for a 1-kb change in telomere length for each telomere length-associated variant (Table ). The Y axis (G–Y association) plots the β-estimate from the logistic regression model for the association of each variant with NHL risk overall and by the subtype (Table ). Error bars around each β-estimate indicate the uncertainty of effect estimates. A best fit regression line and 95% confidence interval are plotted for NHL overall and each subtype using Mendelian randomization likelihood-based estimates. P-values are from the Mendelian randomization likelihood-based method.